Locoregional Therapy With Combination Regimens Including TACE Generate Excitement in HCC

Anjana Pillai, MD

Locoregional therapy with transarterial chemoembolization (TACE) has been a mainstay option for patients with hepatocellular carcinoma (HCC), but combination therapies with TACE have potential to shake up the treatment paradigm as does transarterial radioembolization with Yttrium-90 (TARE-Y90), according to Anjana Pillai, MD.

Data from the phase 3 EMERALD-1 trial (NCT03778957) presented at the 2024 ASCO Gastrointestinal Cancers Symposium revealed that the addition of durvalumab (Imfinzi) and bevacizumab (Avastin) to TACE (n = 204) improved median progression-free survival (PFS) by 6.8 months vs placebo plus TACE (n = 205) in patients with unresectable hepatocellular carcinoma eligible for embolization (HR, 0.77; 95% CI, 0.61-0.98; P = .032). The 18-month PFS rates were 43.1% vs 28.3%, respectively, and benefit was generally consistent across subgroups examined with the triplet therapy vs TACE plus placebo. Further, median time to progression (TTP) was improved by 12 months with the triplet vs placebo and TACE; median TTP was 22.0 months (95% CI, 16.6-24.9) compared with 10.0 months (95% CI, 7.1-13.6), respectively (HR, 0.63; 95% CI, 0.48-0.82).

“Immunotherapy has completely changed the landscape of HCC,” Pillai said. “We started off with sorafenib [Nexavar] where there was very little movement for over a decade [in terms of progress], and even the initial trials of immunotherapy were somewhat disappointing with the early CheckMate [studies]. But it was the combination immunotherapy trials that started showing double-digit numbers for overall survival data.”

In an interview with OncLive^®, Pillai detailed how the treatment landscape for HCC is evolving, highlighting data from EMERALD-1 and considerations with TACE vs TARE (transarterial radioembolization). In an additional interview, Pillai detailed a patient case study and key takeaways from a presentation she gave at an OncLive^® State of the Science Summit™ on locoregional therapies for HCC. Pillai is a professor of medicine and surgery, co-director of the Living Donor Liver Transplant Program, medical director of the Liver Tumor Program, and program director of the Transplant Hepatology Fellowship Program all at UChicago Medicine in Illinois.

OncLive: How has immunotherapy affected the HCC treatment paradigm?

Pillai: Similar to the EMERALD-1 trial, now we’re looking at combining immunotherapy with either TACE or TARE. There are several other phase 3 trials looking at combination arms for unresectable HCC and some are looking at TARE with immunotherapy. One small study was published in Gut in 2023 looking at 49 patients with HCC who underwent TARE or Y90.

Investigators looked at the blood immune monitoring over time and saw that Y90 may have altered the innate immune response and increased the frequency of activated CD3-[positive] T cells and CD8-[positive] subsets. It may be that using immunotherapy within that 1-month [period] post Y90, because that’s when the [investigators] saw the peak of increased CD3 T cells and CD8 subset activity, [could] hopefully will give patients enhanced immunity to fight the cancer. That’s very exciting.

Those are changes we’re hoping for with a combination of immunotherapy and either TARE, TACE, or stereotactic body radiation therapy. We have smaller studies that are showing some of those effects [as well].

What were the key findings from the EMERALD-1 trial?

EMERALD-1 tested TACE in several arms—either with durvalumab; durvalumab and bevacizumab; or placebo. The key finding was that if patients received durvalumab, bevacizumab, and TACE vs placebo and TACE, the PFS was 15.0 months vs 8.2 months, [respectively]. Median PFS was improved by 6.8 months with durvalumab plus bevacizumab and TACE vs placebo and TACE.

For durvalumab and TACE vs placebo and TACE, there was no significant difference in PFS. It was 10.0 months for durvalumab plus TACE vs 8.2 months for placebo plus TACE. It appears the combination arm of durvalumab, bevacizumab, and TACE did very well, [but] the combination arm also had slightly more adverse effects [AEs] as you would expect.

What are the considerations for treatment with TACE vs DEB-TACE?

Center experience matters the most, but the difference between DEB-TACE vs conventional TACE is DEB-TACE [has] beads embedded with doxorubicin and you’re trying to do a more sustained dose delivery ideally with less AEs. Hopefully patients won’t get the post-embolization AEs that occur with TACE. Data from 2 big multicenter prospective trials—the phase 2 PRECISION V [NCT00261378] and [phase 4] PRECISION ITALIA [NCT00936689] studies [published] in 2009 and 2014, respectively—showed that both [TACE and DEB-TACE] work very well. It depends on institutional preference, but DEB-TACE had less [adverse] effects and better tolerability.

What are the next steps needed to push the HCC treatment paradigm forward?

Areas of growth include where neoadjuvant therapy can be applied in HCC as a lot of that data are very early. Looking at adjuvant therapy, the phase 3 IMbrave050 trial [NCT04102098] came out [the data we saw with atezolizumab (Tecentriq) plus bevacizumab in the post resection setting]. Ongoing discussions include: when can you safely use immunotherapy as bridging [therapy] for patients prior to transplant, ie, who would it benefit? Do you need a washout period from the drug, which most of us think there is a need for, to decrease risk of rejection or graft loss, and what is the optimal time [for it]?

It’s interesting because before, it was very dogmatic and treatment went from one stage to the other, but now we’re seeing that instead of nice buckets, you can mix and match therapies and patients can have regression of advanced cancer vs only progression. We may be able to treat with immunotherapy possibly earlier on in early-stage disease and perhaps use locoregional therapy in later stage disease. That paradigm is evolving of when you can use either.

It’s a very exciting time for liver cancer [treatments because] there’s so much movement and growth. Previously, our patients did not have many [treatment options] especially as I was doing fellowship and finishing fellowship. It was always TACE and sorafenib [offered] and we didn’t see great long-term outcomes, but now we’re seeing all these new therapies and improved survival data. The single tremelimumab [Imjudo] regular interval durvalumab [STRIDE] regimen had 4-year survival data [from the phase 3 HIMALAYA study (NCT03298451) demonstrate that] 1 in 4 patients were still alive following treatment. It’s an exciting time and the community overall is looking forward to the data that are coming from a lot of these pending trials.

Reference

Lencioni R, Kudo M, Erinjeri J, et al. EMERALD-1: a phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. J Clin Oncol. 2024;42(suppl 3):LBA432. doi:10.1200/JCO.2024.42.3_suppl.LBA432